The Finnish Mental Hospital Study (4), the Los Angeles Veterans Study (2), and the Oslo

Diet Heart Study (3) all showed that a high polyunsaturated fat intake (13%, 16%, and 21% of total energy, respectively) in the context of saturated fat intake of 9% and total fat intake of 35 40% of energy was associated with significant decreases in CVD events. In contrast, the British Medical Research Council Soy Oil Intervention (10) and the Minnesota Coronary Survey (11) showed nonsignificant effects of replacement of saturated fat with polyunsaturated fat on CVD. 2. Dayton S, Pearce M, Hashimoto S, et al A controlled clinical trial of a diet high in unsaturated fat in preventing complications of atherosclerosis. Circulation 1969;40(suppl II):II-1 63. 3. Leren P. The Oslo Diet-Heart Study: eleven-year report. Circulation 1970;42:935 42. 4. Turpeinen O, Karvonen MJ, Pekkarinen M, Miettinen M, Elosuo R, Paavilainen E. Dietary prevention of coronary heart disease: the Finnish Mental Hospital Study. Int J Epidemiol 1979;8:99 118.

Siri-Tarino 2010 Saturated fat, carbohydrate, and cardiovascular disease

There are differences between individual types of saturated fatty acids with regard to effects on LDL and HDL cholesterol (67). Specifically, there is a progressively smaller LDL-cholesterol-raising effect with substitution for carbohydrate of saturated fatty acids of increasing chain length, with the largest increase observed for lauric acid (12 carbons), and no significant increase with stearic acid (18 carbons). However, lauric acid substitution also results in the greatest increase in HDL cholesterol, such that there is significant lowering of the total: HDL-cholesterol ratio (67). 67. Mensink RP, Zock PL, Kester AD, Katan MB. Effects of dietary fatty acids and carbohydrates on the ratio of serum total to HDL cholesterol and on serum lipids and apolipoproteins: a metaanalysis of 60 controlled trials. Am J Clin Nutr 2003;77:1146 55.

In recent years, there has been increasing concern regarding dietary effects on dyslipidemia, characterized by elevated triglycerides, low concentrations of HDL cholesterol, and increased concentrations of small, dense LDL particles (68). This metabolic profile is considered to be a major contributor to increased CVD risk in patients with the metabolic syndrome, insulin resistance, and type 2 diabetes. Both increased adiposity (69) and higher carbohydrate intakes (6) have been shown to increase the magnitude of each of the components of atherogenic dyslipidemia. 68. Krauss RM. Siri PWb. Metabolic abnormalities: triglyceride and low-density lipoprotein. Endocrinol Metab Clin North Am 2004;33:405 15. 69. Grundy SM. Atherogenic dyslipidemia associated with metabolic syndrome and insulin resistance. Clin Cornerstone 2006;8(suppl 1):S21 7.

We recently conducted a study to evaluate the effects of dietary carbohydrate restriction (from 54% to 26%) with low and high saturated fat (derived primarily from dairy products) in the context of both weight loss and weight stability (8). Carbohydrate restriction under weight-stable conditions reduced total:HDL cholesterol, apolipoprotein B, and the mass of small, dense LDL particles (Figure 1). Weight loss without restriction of carbohydrates led to similar changes (8).

8. Krauss RM, Blanche PJ, Rawlings RS, Fernstrom HS, Williams PT. Separate effects of reduced carbohydrate intake and weight loss on atherogenic dyslipidemia. Am J Clin Nutr 2006;83:1025 31, quiz 1205.

FIGURE 1. Mean (+/-SEM) effects of variation in dietary carbohydrate and saturated fat on LDL subclasses. A cohort of 178 men were randomly assigned to 1 of 4 diet groups: diets with varying carbohydrate contents (54%, 39%, or 26% of total energy) and a low saturated fat content ( , 8% of total energy derived primarily from dairy products) or a diet with a relatively low carbohydrate (26%) and a high saturated fat content ( , 15% of total energy) (8). In the context of the 26% carbohydrate diet, high dietary saturated fat was associated with increases in large and medium LDL, but not with small LDL, relative to diets with a lower saturated fat content. Data points represent biochemical profiles for each of the 4 dietary groups. Values are the total lipoprotein mass as measured by analytic ultracentrifugation.

Siri-Tarino 2010 Saturated fat, carbohydrate, and cardiovascular disease

The type of dietary carbohydrate consumed may affect lipid and lipoprotein profiles (74, 75), Recent studies showed that, compared with dietary saturated fat, the saturated fat to fiber ratio was a stronger predictor of lipoprotein response in persons consuming beef or vegetarian diets (76). 74. Pelkman CL. Effects of the glycemic index of foods on serum concentrations of high-density lipoprotein cholesterol and triglycerides. Curr Atheroscler Rep 2001;3:456 61. 75. Jenkins DJ, Kendall CW, Augustin LS, Vuksan V. High-complex carbohydrate or lente carbohydrate foods? Am J Med 2002;113(suppl 9B): 30S 7S. 76. Haub MD, Wells AM, Campbell WW. Beef and soy-based food supplements differentially affect serum lipoprotein-lipid profiles because of changes in carbohydrate intake and novel nutrient intake ratios in older men who resistive-train. Metabolism 2005;54:769 74.

LDL and HDL particles of different sizes and compositions derive from many metabolic pathways, and smaller and more dense LDL particles have been implicated as being more strongly involved in atherosclerotic CVD than larger LDL particles, as reviewed elsewhere (78). 78. Berneis KK, Krauss RM. Metabolic origins and clinical significance of LDL heterogeneity. J Lipid Res 2002;43:1363 79. The reduction in LDL cholesterol known to occur with a decreased saturated fat intake appears to be specific to larger more buoyant particles (79). In persons placed on a baseline highsaturated-fat diet and then switched to a diet high in monounsaturated or polyunsaturated fat, a small but significant reduction in LDL particle size was observed (80). 79. Dreon DM, Fernstrom HA, Campos H, Blanche P, Williams PT, Krauss RM. Change in dietary saturated fat intake is correlated with change in mass of large low-density-lipoprotein particles in men. Am J Clin Nutr 1998;67:828 36. 80. Kratz M, Gulbahce E, von Eckardstein A, et al. Dietary mono- and polyunsaturated fatty acids similarly affect LDL size in healthy men and women. J Nutr 2002;132:715 8.

Factors affecting variation in lipoprotein response to saturated Fat There is considerable interindividual variability in the lipoprotein response to variations in saturated fat intake, and this is related to some extent to variation in response to dietary cholesterol, which suggests a role for intrinsic differences in the regulation of lipid metabolism (88, 89). Other factors that have been reported to be associated with a reduced LDL response to reductions in saturated fat include increased BMI (91), 88. Beynen AC, Katan MB, Van Zutphen LF. Hypo- and hyperresponders: individual differences in the response of serum cholesterol concentration to changes in diet. Adv Lipid Res 1987;22:115 71. 89. Katan MB, van Gastel AC, de Rover CM, van Montfort MA, Knuiman JT. Differences in individual responsiveness of serum cholesterol to fat-modified diets in man. Eur J Clin Invest 1988;18:644 7. 91. Jansen S, Lopez-Miranda J, Salas J, et al. Plasma lipid response to hypolipidemic diets in young healthy non-obese men varies with body mass index. J Nutr 1998;128:1144 9.

Genetic factors may also contribute to variability in the dietary response to saturated fat (96 98). Among these, the apoE4 isoform, which is associated with increased plasma LDL cholesterol in comparison with the more common apoE3 isoform, has been most consistently found to be predictive of a greater LDL-cholesterol reduction in response to diet (99, 100). 96. Ordovas JM. Nutrigenetics, plasma lipids, and cardiovascular risk. J Am Diet Assoc 2006;106:1074 81, quiz 1083. 97. Denke MA, Adams-Huet B, Nguyen AT. Individual cholesterol variation in response to a margarine- or butter-based diet: a study in families. JAMA 2000;284:2740 7. 98. Krauss RM, Dreon DM. Low-density-lipoprotein subclasses and response to a low-fat diet in healthy men. Am J Clin Nutr 1995; 62(suppl):478S 87S. 99. Ordovas JM, Lopez-Miranda J, Mata P, Perez-Jimenez F, Lichtenstein AH, Schaefer EJ. Genediet interaction in determining plasma lipid response to dietary intervention. Atherosclerosis 1995;118(suppl): S11 27. 100. Dreon DM, Fernstrom HA, Miller B, Krauss RM. Apolipoprotein E isoform phenotype and LDL subclass response to a reduced-fat diet. Arterioscler Thromb Vasc Biol 1995;15:105 11.

it is of interest that the effects of dairy-derived fat on lipids and lipoproteins have been reported to differ between specific types of dairy food sources (101). 101. German JB, Gibson RA, Krauss RM, et al. A reappraisal of the impact of dairy foods and milk fat on cardiovascular disease risk. Eur J Nutr 2009;48:191 203. Blood pressure The effect of saturated fat on blood pressure has not been definitively established, although a study in 162 healthy persons showed that a diet high in monounsaturated fat decreased blood pressure, whereas a diet high in saturated fat led to no change in blood pressure (102). 102. Rasmussen BM, Vessby B, Uusitupa M, et al. Effects of dietary saturated, monounsaturated, and n23 fatty acids on blood pressure in healthy subjects. Am J Clin Nutr 2006;83:221 6.

Insulin sensitivity in the Nurses Health Study, total, saturated, and monounsaturated fats were not associated with risk of type 2 diabetes, whereas polyunsaturated fats decreased the risk and trans fats increased the risk (113). Similarly, in the Health Professionals Follow-Up Study, saturated fat was not associated with risk of type 2 diabetes after adjustment for BMI (114). Furthermore, in most human intervention studies, changes in dietary fat quality had no effects on insulin sensitivity (106, 115). 106. Riccardi G, Giacco R, Rivellese AA. Dietary fat, insulin sensitivity and the metabolic syndrome. Clin Nutr 2004;23:447 56. 113. Salmeron J, Hu FB, Manson JE, et al. Dietary fat intake and risk of type 2 diabetes in women. Am J Clin Nutr 2001;73:1019 26. 114. van Dam RM,Willett WC, Rimm EB, Stampfer MJ, Hu FB. Dietary fat and meat intake in relation to risk of type 2 diabetes in men. Diabetes Care 2002;25:417 24. 115. Manco M, Calvani M, Mingrone G. Effects of dietary fatty acids on insulin sensitivity and secretion. Diabetes Obes Metab 2004;6:402 13.

However, the effect of saturated fat on insulin sensitivity may be modulated by the total amount of fat in the diet (116). In a randomized clinical trial of 162 healthy persons, no differences in insulin sensitivity were observed between persons consuming saturated fat enriched or monounsaturated fat enriched diets when total fat intake represented >37% of total energy; in contrast, in persons who consumed lower total fat intakes, saturated fat led to decreased insulin sensitivity compared with monounsaturated fat (116). In other studies, there have been no consistent effects on insulin sensitivity of variations in total fat intake between 20% and 40% of total energy intake without changes in fatty acid composition (107, 117). 107. Rivellese AA, Maffettone A, Vessby B, et al. Effects of dietary saturated, monounsaturated and n-3 fatty acids on fasting lipoproteins, LDL size and post-prandial lipid metabolism in healthy subjects. Atherosclerosis 2003;167:149 58. 116. Vessby B, Unsitupa M, Hermansen K, et al. Substituting dietary saturated for monounsaturated fat impairs insulin sensitivity in healthy men and women: the KANWU Study. Diabetologia 2001;44: 312 9. 117. Howard BV. Dietary fat and diabetes: a consensus view. Am J Med 2002;113(suppl 9B):38S 40S.

there is a growing body of evidence from cellular and animal studies that supports the proinflammatory effects of saturated fat, as reviewed extensively elsewhere (108). 108. Kennedy A, Martinez K, Chuang CC, LaPoint K, McIntosh M. Saturated fatty acid-mediated inflammation and insulin resistance in adipose tissue: mechanisms of action and implications. J Nutr 2009;139: 1 4. 121. Erridge C, Samani NJ. Saturated fatty acids do not directly stimulate Toll-like receptor signaling. Arterioscler Thromb Vasc Biol 2009;29: 1944 9. In the acute postprandial phase following a meal enriched in saturated or polyunsaturated fat, HDL collected from individuals after a coconut meal compared with a safflower or unsaturated fat meal was associated with a 50 70% increase in intercellular adhesion molecule and vascular cell adhesion molecule (131). Attribution of this effect specifically to the saturated fat of the coconut meal may, however, be confounded by the high concentrations of tocopherol found in coconut oil (132). 131. Nicholls SJ, Lundman P, Harmer JA, et al. Consumption of saturated fat impairs the antiinflammatory properties of high-density lipoproteins and endothelial function. J Am Coll Cardiol 2006;48:715 20. 132. Masterjohn C. The anti-inflammatory properties of safflower oil and coconut oil may be mediated by their respective concentrations of vitamin E. J Am Coll Cardiol 2007;49:1825 6.